Decoding Brain Somatic Mosaicism with New Single-Cell Copy Number Analysis Methods

Copy number variants (CNVs) represent a significant but understudied form of somatic variation in the human brain, with potential implications for neurodevelopment, aging and disease. While single-cell whole-genome sequencing (scWGS) enables genome-wide profiling at single-cell resolution, existing computational methods struggle to accurately detect non-clonal CNVs, limiting our understanding of genomic mosaicism in the brain. In this thesis, I present two novel and complementary computational approaches for high-resolution CNV analysis in single cells. The first, HiScanner, is a CNV detection method that integrates single-cell assay-specific characteristics and introduces innovations in bin size optimization, read depth normalization, and joint segmentation across cells. Through extensive benchmarking experiments, I demonstrate HiScanner’s superior performance compared to existing tools. The second is a validation method that leverages unique molecular patterns from tagmentation-based scWGS, representing the first tool that exploits fragment overlap patterns to corroborate CNV predictions. I then apply these tools to investigate CNVs in three biological contexts: tumor evolution in paired initial and recurrent meningiomas, age-related genomic changes in neurotypical human brains, and developmental patterns in fetal and postnatal brain tissues. By analyzing both scWGS and multimodal single-cell data (paired RNA-seq and ATAC-seq), I characterize cell-type-specific CNV patterns and their potential functional implications. This work establishes a robust framework for studying somatic CNVs at single-cell resolution and provides insights into genomic instability in brain development, aging, and disease.

Name thesis:degree_name

Doctoral

Department dc:contributor.department

Harvard-MIT Program in Health Sciences and Technology

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2025

Author dc:creator

• Zhao, Yifan

Advisor dc:contributor.advisor

• Park, Peter J.

Statement dc:rights

• In Copyright - Educational Use Permitted
• Copyright retained by author(s)

Licence dc:rights.uri

• https://rightsstatements.org/page/InC-EDU/1.0/

Handle dc:identifier.uri

https://hdl.handle.net/1721.1/162300

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/162300